U.S. Pat. No. 5,229,382 (hereinafter described as '382) discloses the preparation of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, or an acid addition salt thereof by reacting N-methyl piperazine with 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride. The anhydrous 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine obtained by the process of this patent is referred to herein as Form I. Form I has been reported to be metastable and to change its colour on standing thus being unsuitable for commercial use in pharmaceutical formulation.
U.S. Pat. No. 5,736,541 (hereinafter described as '541) claims a novel crystal form (Form II) of olanzapine which is substantially pure, solvate free, anhydrous and pharmaceutically elegant. This novel crystal form is free from Form I and contamination by solvates such as water or acetonitrile and has satisfactory colour stability. The '541 patent provides olanzapine Form II having a typical x-ray powder diffraction pattern as represented by the d (interplanar spacing) values: 10.2689, 8.577, 7.4721, 7.125, 6.1459, 6.071, 5.4849, 5.2181, 5.1251, 4.9874, 4.7665, 4.7158, 4.4787, 4.3307, 4.2294, 4.141, 3.9873, 3.7206, 3.5645, 3.5366, 3.3828, 3.2516, 3.134, 3.0848, 3.0638, 3.0111, 2.8739, 2.8102, 2.7217, 2.6432, 2.6007.
Further, this patent designates the polymorph obtained by the process disclosed in '382 patent as Form I having a typical x-ray powder diffraction pattern as represented by the d (interplanar spacing) values : 9.9463, 8.5579, 8.2445, 6.8862, 6.3787, 6.2439, 5.5895, 5.3055, 4.9815, 4.8333, 4.7255, 4.6286, 4.533, 4.4624, 4.2915, 4.2346, 4.0855, 3.8254, 3.7489, 3.6983, 3.5817, 3.5064, 3.3392, 3.2806, 3.2138, 3.1118, 3.0507, 2.948, 2.8172, 2.7589, 2.6597, 2.6336, 2.5956.
The nomenclature referred to in this patent for crystalline forms of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine is adopted herein.
The process disclosed in the '541 patent consists of obtaining technical grade olanzapine (that is olanzapine containing less than about 5% undesired related substances and preferably less than 1% undesired related substances) by adding water to a methanolic reaction mixture and filtering the solids. The technical grade olanzapine obtained is crystallized from anhydrous ethyl acetate as substantially pure Form II that is free from the undesired crystal Form I or solvates such as water, alcohol, ethylacetate or acetonitrile.
U.S. Pat. No. 5,703,232 (hereinafter described as '232) relates to lower alcohol solvates of olanzapine and a process for using such lower alcohol solvates to prepare anhydrous olanzapine crystalline form having a typical x-ray diffraction pattern with d (interplanar spacing) values substantially as follows 10.2689, 8.577, 7.4721, 7.125, 6.1459, 6.071, 5.4849, 5.2181, 5.1251, 4.9874, 4.7665, 4.7158, 4.4787, 4.3307, 4.2294, 4.141, 3.0873, 3.7206, 3.5645, 3.5366, 3.3828, 3.2516, 3.134, 3.0848, 3.0638, 3.0111, 2.8739, 2.8102, 2.7217, 2.6432, 2.6007. The patent labels this crystalline form as Form I and reverses the nomenclature adopted in the '541 patent. As compared to the '541 process where a technical grade olanzapine is precipitated by addition of excess water to a methanolic reaction mixture, the '232 process involves addition of a C1-C3 alcohol and isolating an alkanol solvate by cooling. The anhydrous crystalline form of olanzapine is prepared by recrystallizing the alkanol solvate from an appropriate solvent. The patent does not disclose anhydrous olanzapine crystalline form having a typical x-ray powder diffraction pattern as represented by d (interplanar spacing) values 9.9446, 8.5272, 8.1949, 6.8637, 6.3510, 5.4653, 4.8278, 4.7121, 4.5295, 4.2239, 4.0788, 3.8230, 3.7525, 3.6909, 3.4995, 3.3393, 3.1051, 2.9451, 2.8182, 2.7589, 2.5925, 2.3369, 2.0251, 1.9183; infrared absorbance bands at approximately 1456, 1365, 905, 757, 662 & 604 cm−1and having a stable colour upon storage under ambient conditions or a process for its preparation using two or more repetitive crystallization steps.
The above patents do not disclose anhydrous olanzapine crystalline form I having a stable colour upon storage under ambient conditions or a process for its preparation using two or more repetitive crystallization steps.
WO 9812199 relates to the dihydrate of olanzapine. Dihydrates B, D and E are claimed as intermediates for preparing Form II. The dihydrates are dried for a period of about 27-30 hours to yield olanzapine Form II.
Prior art suggests that Form I olanzapine is pharmaceutically unsuitable because its colour changes upon storage and exposure to air. Methods like charcoal treatment to remove undesired colour from the Form I olanzapine prepared by '382 were not successful. Anhydrous olanzapine crystalline Form I having a stable colour upon storage at ambient conditions is hitherto unknown.